The chloroplast-localized casein kinase II α subunit, CPCK2, negatively regulates plant innate immunity through promoting S-nitrosylation of SABP3.

The casein kinase II (CK2) complex consists of catalytic (α) and regulatory (ß) subunits and is highly conserved throughout eukaryotes. Plant CK2 plays critical roles in multiple physiological processes; however, its function in plant immunity remains obscure. In this study, we demonstrated that the unique chloroplast-localized CK2 α subunit (CPCK2) is a negative regulator of Arabidopsis thaliana innate immunity. cpck2 mutants displayed enhanced resistance against the fungal pathogen powdery mildew, Golovinomyces cichoracearum and the virulent bacterial pathogen, Pseudomonas syringae pv. tomato (Pto) DC3000. Moreover, the cpck2-1 mutant accumulated higher salicylic acid (SA) levels and mutations that disabled SA biosynthesis or signaling inhibited cpck2-1-mediated disease resistance. CPCK2 interacted with the chloroplast-localized carbonic anhydrase (CA), SA-binding protein 3 (SABP3), which was required for cpck2-mediated immunity. Significantly, CPCK2 phosphorylated SABP3, which promoted S-nitrosylation of this enzyme. It has previously been established that S-nitrosylation of SABP3 reduces both its SA binding function and its CA activity, which compromises the immune-related function of SABP3. Taken together, our results establish CPCK2 as a negative regulator of SA accumulation and associated immunity. Importantly, our findings unveil a mechanism by which CPCK2 negatively regulates plant immunity by promoting S-nitrosylation of SABP3 through phosphorylation, which provides the first example in plants of S-nitrosylation being promoted by cognate phosphorylation.

NRSF regulates age-dependently cognitive ability and its conditional knockout in APP/PS1 mice moderately alters AD-like pathology.

NRSF/REST (neuron-restrictive silencer element, also known as repressor element 1-silencing transcription factor), plays a key role in neuronal homeostasis as a transcriptional repressor of neuronal genes. NRSF/REST relates to cognitive preservation and longevity of humans, but its specific functions in age-dependent and Alzheimer's disease (AD)-related memory deficits remain unclear. Here, we show that conditional NRSF/REST knockout either in the dorsal telencephalon or specially in neurons induced an age-dependently diminished retrieval performance in spatial or fear conditioning memory tasks and altered hippocampal synaptic transmission and activity-dependent synaptic plasticity. The NRSF/REST deficient mice were also characterized by an increase of activated glial cells, complement C3 protein and the transcription factor C/EBPß in the cortex and hippocampus. Reduction of NRSF/REST by conditional depletion upregulated the activation of astrocytes in APP/PS1 mice, and increased the C3-positive glial cells, but did not alter the Aß loads and memory retrieval performances of 6- and 12-month-old APP/PS1 mice. Simultaneously, overexpression of NRSF/REST improved cognitive abilities of aged wild type, but not in AD mice. These findings demonstrated that NRSF/REST is essential for the preservation of memory performance and activity-dependent synaptic plasticity during aging and takes potential roles in the onset of age-related memory impairments. However, while altering the glial activation, NRSF/REST deficiency does not interfere with the Aß deposits and the electrophysiological and cognitive AD-like pathologies.

A nuclear import pathway exploited by pathogenic noncoding RNAs.

The prevailing view of intracellular RNA trafficking in eukaryotic cells is that RNAs transcribed in the nucleus either stay in the nucleus or cross the nuclear envelope, entering the cytoplasm for function. However, emerging evidence illustrates that numerous functional RNAs move in the reverse direction, from the cytoplasm to the nucleus. The mechanism underlying RNA nuclear import has not been well elucidated. Viroids are single-stranded circular noncoding RNAs that infect plants. Using Nicotiana benthamiana, tomato (Solanum lycopersicum), and nuclear-replicating viroids as a model, we showed that cellular IMPORTIN ALPHA-4 (IMPa-4) is likely involved in viroid RNA nuclear import, empirically supporting the involvement of Importin-based cellular pathway in RNA nuclear import. We also confirmed the involvement of a cellular protein (viroid RNA-binding protein 1 [VIRP1]) that binds both IMPa-4 and viroids. Moreover, a conserved C-loop in nuclear-replicating viroids serves as a key signal for nuclear import. Disrupting C-loop impairs VIRP1 binding, viroid nuclear accumulation, and infectivity. Further, C-loop exists in a subviral satellite noncoding RNA that relies on VIRP1 for nuclear import. These results advance our understanding of subviral RNA infection and the regulation of RNA nuclear import.

Phosphorylation of OsTGA5 by casein kinase II compromises its suppression of defense-related gene transcription in rice.

Plants manage the high cost of immunity activation by suppressing the expression of defense genes during normal growth and rapidly switching them on upon pathogen invasion. TGAs are key transcription factors controlling the expression of defense genes. However, how TGAs function, especially in monocot plants like rice with continuously high levels of endogenous salicylic acid (SA) remains elusive. In this study, we characterized the role of OsTGA5 as a negative regulator of rice resistance against blast fungus by transcriptionally repressing the expression of various defense-related genes. Moreover, OsTGA5 repressed PTI responses and the accumulation of endogenous SA. Importantly, we showed that the nucleus-localized casein kinase II (CK2) complex interacts with and phosphorylates OsTGA5 on Ser-32, which reduces the affinity of OsTGA5 for the JIOsPR10 promoter, thereby alleviating the repression of JIOsPR10 transcription and increasing rice resistance. Furthermore, the in vivo phosphorylation of OsTGA5 Ser-32 was enhanced by blast fungus infection. The CK2 α subunit, depending on its kinase activity, positively regulated rice defense against blast fungus. Taken together, our results provide a mechanism for the role of OsTGA5 in negatively regulating the transcription of defense-related genes in rice and the repressive switch imposed by nuclear CK2-mediated phosphorylation during blast fungus invasion.

Association of sdLDL-C With Incident Carotid Plaques With Stable and Vulnerable Morphology: A Prospective Cohort Study.

BACKGROUND: Small dense low-density lipoprotein cholesterol (sdLDL-C) particles are more atherogenic than large and intermediate low-density lipoprotein cholesterol (LDL-C) subfractions. We sought to investigate the association of sdLDL-C and the sdLDL-C/LDL-C ratio with incident carotid plaques with stable and vulnerable morphology in rural China. METHODS: This community-based cohort study used data from the RICAS study (Rose Asymptomatic Intracranial Artery Stenosis), which enrolled 887 participants (aged ≥40 years) who were living in Kongcun Town, Pingyin County, Shandong, and free of carotid plaques and had no history of clinical stroke or transient ischemic attack at baseline (2017). Incident carotid plaques and their vulnerability were detected by carotid ultrasound at follow-up (2021). Multivariable logistic regression models were used to explore the association of sdLDL-C or sdLDL-C/LDL-C ratio with incident carotid plaques while adjusting for demographic factors, vascular risk factors, and follow-up time. RESULTS: Of the 887 participants (mean age [SD], 53.89 [8.67%] years; 54.34% women), 179 (20.18%) were detected with incident carotid plaques during an average follow-up of 3.94 years (SD=0.14). Higher sdLDL-C or sdLDL-C/LDL-C ratio, but not LDL-C, was significantly associated with an increased risk of incident carotid plaques. The upper tertile of sdLDL-C (versus lower tertile) was associated with the multivariate-adjusted odds ratio of 2.48 (95% CI, 1.00-6.15; P=0.049; P for linear trend=0.046) for carotid plaques with vulnerable morphology (n=41), and the association remained significant in participants with normal LDL-C (<130 mg/dL; n=693; upper versus lower tertile: odds ratio, 3.38 [95% CI, 1.15-9.90]; P=0.027; P for linear trend=0.025). Moreover, the sdLDL-C/LDL-C ratio was associated with a higher odds ratio of incident carotid plaques in participants without diabetes (P for interaction=0.014). CONCLUSIONS: Higher sdLDL-C was associated with an increased risk of incident carotid plaques, especially carotid plaques with vulnerable morphology, even in participants with normal LDL-C. This suggests the potential of sdLDL-C as a therapeutic target for stroke prevention. REGISTRATION: URL: https://www.chictr.org.cn; Unique identifier: ChiCTR1800017197.

Remission of organ failure in patients with predicted severe acute pancreatitis treated by somatostation, octreotide and cyclooxygenase-2 inhibitors.

BACKGROUND: /Objectives: Persistent organ failure (OF) in severe acute pancreatitis (SAP) is caused by activation of cytokine cascades, resulting in inflammatory injury. Anti-inflammation may be helpful in OF remission in early SAP. To assess the efficacy of anti-inflammatory regimens for OF prevention and remission in patients with predicted SAP and display clinical doctors' acceptance of these strategies, we conducted this retrospective study in the real world. METHODS: Clinical data of patients with predicted SAP from 2010 to 2017 were retrospectively reviewed. Cases were divided into conventional support (C), C+ somatostatin/octreotide (C + S/O), and C + S/O + Cyclooxygenase-2-inhibitors (C + S/O + COX-2-I). The occurrence of SAP, OF, changes of proportion for three strategies, length of hospital stay, meperidine injection, and cytokine levels were compared. The constituent ratios of the three schemes over eight years were evaluated. RESULTS: A total of 580 cases (C = 124, C + S/O = 290, C + S/O + COX-2-I = 166) were included. The occurrences of SAP in the C + S/O (28.3 %) and C + S/O + COX-2-I (18.1 %) groups were significantly lower than that in C group (60.5 %, P < 0.001), mainly by reducing persistent respiratory failure (P < 0.001) and renal failure (P = 0.002). C + S/O and C + S/O + COX-2-I regimens significantly decreased new onset OF and enhanced OF amelioration within 48 h when compared with C treatment (P < 0.001) in patients with OF score <2 and ≥ 2 on admission, respectively. C + S/O and C + S/O + COX-2-I as compared with C group significantly decrease OF occurrences in a multivariate logistic regression analysis (P < 0.05). CONCLUSIONS: Somatostatin or its analogs and cyclooxygenase-2 inhibitors are promising for OF prevention and remission in patients with predicted SAP. The acceptance of combined strategies in the real world has increased, and the occurrence of SAP has decreased annually.

Evaluation of effects from hemoglobin variants on HbA1c measurements by different methods.

OBJECTIVES: The impact of seven hemoglobin variants (Hb Q-Thailand, Hb G-Honolulu, Hb Ube-2, Hb New York, Hb J-Bangkok, Hb G-Coushatta, and Hb E) on the outcome of HbA1c was investigated for six methods by comparing with liquid chromatography-tandem mass spectrometry (LC/MS/MS) reference method. METHODS: Twenty-nine normal and 112 variant samples were measured by LC/MS/MS, Sebia Capillarys 3 TERA, Intelligene Biosystems QuanTOF, Premier Hb9210, Arkray HA-8190V, Bio-Rad D-100, and Tosoh G11, then evaluated for correlation, consistency, and mean relative bias among six methods. The lowest biological variation bias of ±2.8 % was an acceptable standard. RESULTS: All methods showed poor correlation and consistency with LC/MS/MS for Hb E. The unacceptable biases were observed for Capillarys 3 TERA (-14.4 to -3.7 % for Hb Q-Thailand, Hb Ube-2, Hb New York, Hb J-Bangkok and Hb E), QuanTOF (-8.3 to -2.9 % for Hb Ube-2, Hb New York and Hb G-Coushatta), Premier Hb9210 (-18.3 to -3.6 % for Hb Q-Thailand, Hb Ube-2, Hb New York, Hb J-Bangkok and Hb E), HA-8190V variant mode (-17.3 to 6.6 % for Hb G-Honolulu, Hb Ube-2, Hb New York, Hb G-Coushatta and Hb E). All variant samples showed larger biases than ±2.8 % comparing HA-8190V fast mode, D-100, and G11 with LC/MS/MS. CONCLUSIONS: The accuracy of different HbA1c methods was influenced by some Hb variants, especially Hb Ube-2 and Hb New York. Thus, laboratories need to choose appropriate methods to measure HbA1c with different Hb variants.

Are children with IgA nephropathy different from adult patients?

BACKGROUND: Previously, several studies have indicated that pediatric IgA nephropathy (IgAN) might be different from adult IgAN, and treatment strategies might be also different between pediatric IgAN and adult IgAN. METHODS: We analyzed two prospective cohorts established by pediatric and adult nephrologists, respectively. A comprehensive analysis was performed investigating the difference in clinical and pathological characteristics, treatment, and prognosis between children and adults with IgAN. RESULTS: A total of 1015 children and 1911 adults with IgAN were eligible for analysis. More frequent gross hematuria (88% vs. 20%, p < 0.0001) and higher proteinuria (1.8 vs. 1.3 g/d, p < 0.0001) were seen in children compared to adults. In comparison, the estimated glomerular filtration rate (eGFR) was lower in adults (80.4 vs. 163 ml/min/1.73 m2, p < 0.0001). Hypertension was more prevalent in adult patients. Pathologically, a higher proportion of M1 was revealed (62% vs. 39%, p < 0.0001) in children than in adults. S1 (62% vs. 28%, p < 0.0001) and T1-2 (34% vs. 8%, p < 0.0001) were more frequent in adults. Adjusted by proteinuria, eGFR, and hypertension, children were more likely to be treated with glucocorticoids than adults (87% vs. 45%, p < 0.0001). After propensity score matching, in IgAN with proteinuria > 1 g/d, children treated with steroids were 1.87 (95% CI 1.16-3.02, p = 0.01) times more likely to reach complete remission of proteinuria compared with adults treated with steroids. CONCLUSIONS: Children present significantly differently from adults with IgAN in clinical and pathological manifestations and disease progression. Steroid response might be better in children.

Impact of European Union label changes to avoid inadvertent use of medicinal products containing methotrexate for once-weekly administration: A survey amongst prescribers, pharmacists and patients on awareness, knowledge, and behaviour.

PURPOSE: To determine the effectiveness of risk minimisation measures (RMM) to avoid inadvertent daily instead of weekly methotrexate (MTX) use, introduced by the European Medicines Agency (EMA) from 2019 onwards. METHODS: Using a cross-sectional online survey in France, Greece, Germany, Poland, and Sweden in 2022, we assessed awareness, knowledge, and self-declared behaviour for respondents who prescribed, dispensed, or used once-weekly MTX in the last 3 months. Respondents' answers were considered as 'successful' with regards to RMM effectiveness (vs. unsuccessful) if they provided correct ('desirable') responses to 100% of questions regarding awareness and self-declared behaviour and correct responses to ≥80% of questions about knowledge. Per target population, an outcome was considered successful if achieved by ≥80% of respondents. Effectiveness of RMM was defined by ≥80% being successful on all outcomes. RESULTS: One-hundred-fifty-one prescribers, 150 pharmacists, and 150 patients completed the survey. Success rates were 56% (95% CI 48.0%-64.3%) for awareness, 42% (95% CI 34.4%-50.7%) for knowledge, and 31% (95% CI 23.8%-39.2%) for self-declared behaviour among prescribers, 18% (95% CI 12.8%-25.8%) for awareness, 7% (95% CI 3.7%-12.7%) for knowledge, and 50% (95% CI 41.7%-58.3%) for self-declared behaviour among pharmacists, and 29% (95% CI 21.6%-36.6%) for awareness, and 3% (95% CI 1.1%-7.6%) for knowledge among patients. Overall success was not attained by any target population. CONCLUSIONS: RMM were evaluated as not effective across outcomes of awareness, knowledge, and self-declared behaviour in prescribers, pharmacists, and patients. Findings suggested we need continued efforts for RMM across all target populations and across all outcomes.

The association between non­high­density lipoprotein cholesterol to high­density lipoprotein cholesterol ratio (NHHR) and low muscle mass in adults aged 20-59: a population-based study in the United States.

BACKGROUND: The ratio between non-high-density lipoprotein cholesterol and high-density lipoprotein cholesterol (NHHR) is a reliable marker for assessing the risk linked to lipid metabolism disorders. Sarcopenia, characterized by age-related loss of muscle mass and strength/function, includes the assessment of muscle mass, muscle strength, and muscle-specific strength. However, research into NHHR's relationship with low muscle mass risk remains unexplored. METHODS: Our study utilized a cross-sectional approach, examining data derived from the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2018. Through multivariable linear and logistic regression, we investigated the relationships of the NHHR with muscle mass and low muscle mass. We visualized the results using smoothing curves and assessed threshold effects. We also performed various subgroup and sensitivity analyses. RESULTS: This research encompassed 9,012 participants and demonstrated significant nonlinear associations between NHHR and ALMBMI or low muscle mass risk in a generalized additive model (GAM), pinpointing critical NHHR values (3.328 and 3.367) where changes in NHHR significantly impacted ALMBMI and low muscle mass risk. CONCLUSIONS: The NHHR demonstrates a significant association with an increased risk of low muscle mass among middle-aged Americans. This ratio has potential as a predictive marker for low muscle mass. Further exploration of NHHR is expected to aid in advancing preventive and therapeutic measures for this condition.

Mapping trends in hemifacial spasm research: bibliometric and visualization-based analyses of the Web of Science Core Collection.

Hemifacial spasm (HFS) is a common cranial nerve disease. In HFS research, we conducted a bibliometric analysis to examine the development and research trends. A retrieval of HFS studies published between 2011 and 2022 was performed from the Web of Science Core Collection in September 2022. Two scientometric tools were used to perform bibliometric and visualization-based analyses: VOSviewer and CiteSpace. Bibliometric analysis of 1461 studies published between 2011 and 2022 was carried out using data from 444 journals, 6021 authors, 1732 institutions, and 76 countries/regions. China, the USA, Japan, and South Korea were four key contributors to this study. Shanghai Jiaotong University was the major institution with the larger number of publications. Li Shiting was the most prolific author. Jannetta PJ was the most co-cited author. World Neurosurgery was the top prolific journal. Journal of Neurosurgery was the top co-cited journal. The top five keywords were hemifacial spasm, microvascular decompression, trigeminal neuralgia, surgery, and neurovascular compression. This study examines the research trends in global scientific research on HFS over the last decade. Researchers interested in learning more about current trends and novel research frontiers in this area can benefit from the study.

Brain magnetic resonance imaging findings in children with neurological complications of coronavirus disease 2019 (Omicron variant): a multicenter retrospective observational study.

BACKGROUND: An increasing rate of encephalopathy associated with coronavirus disease 2019 (COVID-19) has been observed among children. However, the literature on neuroimaging data in children with COVID-19 is limited. OBJECTIVE: To analyze brain magnetic resonance imaging (MRI) of pediatric COVID-19 patients with neurological complications. MATERIALS AND METHODS: This multicenter retrospective observational study analyzed clinical (n=102, 100%) and neuroimaging (n=93, 91.2%) data of 102 children with COVID-19 infections and comorbid acute neurological symptoms. These children were hospitalized at five pediatric intensive care units (PICUs) in China between December 1, 2022, and January 31, 2023. RESULTS: All patients were positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as detected via reverse transcriptase polymerase chain reaction. About 75.7% of the children were infected with the Omicron variant BF.7 strain. Brain MRI was performed 1-12 days following the onset of neurological symptoms, which revealed acute neuroimaging findings in 74.2% (69/93) of cases, including evidence of acute necrotizing encephalopathy (33/69, 47.8%), encephalitis (31/69, 44.9%), reversible splenial lesion syndrome (3/69, 4.3%), reversible posterior leukoencephalopathy (1/69, 1.4%), and hippocampal atrophy (1/69, 1.4%). CONCLUSIONS: Overall, these data highlighted five neuroimaging patterns associated with the outbreak of the SARS-CoV-2 Omicron variant, with acute necrotizing encephalopathy being the most common of these neuroimaging findings. Rarely, the brain MRI of these pediatric COVID-19 patients also demonstrate hippocampal atrophy.

An in vitro vesicle formation assay reveals cargo clients and factors that mediate vesicular trafficking.

The fidelity of protein transport in the secretory pathway relies on the accurate sorting of proteins to their correct destinations. To deepen our understanding of the underlying molecular mechanisms, it is important to develop a robust approach to systematically reveal cargo proteins that depend on specific sorting machinery to be enriched into transport vesicles. Here, we used an in vitro assay that reconstitutes packaging of human cargo proteins into vesicles to quantify cargo capture. Quantitative mass spectrometry (MS) analyses of the isolated vesicles revealed cytosolic proteins that are associated with vesicle membranes in a GTP-dependent manner. We found that two of them, FAM84B (also known as LRAT domain containing 2 or LRATD2) and PRRC1, contain proline-rich domains and regulate anterograde trafficking. Further analyses revealed that PRRC1 is recruited to endoplasmic reticulum (ER) exit sites, interacts with the inner COPII coat, and its absence increases membrane association of COPII. In addition, we uncovered cargo proteins that depend on GTP hydrolysis to be captured into vesicles. Comparing control cells with cells depleted of the cargo receptors, SURF4 or ERGIC53, we revealed specific clients of each of these two export adaptors. Our results indicate that the vesicle formation assay in combination with quantitative MS analysis is a robust and powerful tool to uncover novel factors that mediate vesicular trafficking and to uncover cargo clients of specific cellular factors.

Cytoplasmic synthesis of endogenous Alu complementary DNA via reverse transcription and implications in age-related macular degeneration.

Alu retroelements propagate via retrotransposition by hijacking long interspersed nuclear element-1 (L1) reverse transcriptase (RT) and endonuclease activities. Reverse transcription of Alu RNA into complementary DNA (cDNA) is presumed to occur exclusively in the nucleus at the genomic integration site. Whether Alu cDNA is synthesized independently of genomic integration is unknown. Alu RNA promotes retinal pigmented epithelium (RPE) death in geographic atrophy, an untreatable type of age-related macular degeneration. We report that Alu RNA-induced RPE degeneration is mediated via cytoplasmic L1-reverse-transcribed Alu cDNA independently of retrotransposition. Alu RNA did not induce cDNA production or RPE degeneration in L1-inhibited animals or human cells. Alu reverse transcription can be initiated in the cytoplasm via self-priming of Alu RNA. In four health insurance databases, use of nucleoside RT inhibitors was associated with reduced risk of developing atrophic macular degeneration (pooled adjusted hazard ratio, 0.616; 95% confidence interval, 0.493-0.770), thus identifying inhibitors of this Alu replication cycle shunt as potential therapies for a major cause of blindness.

Nuclear receptor RXRα binds the precursor of miR-103 to inhibit its maturation.

BACKGROUND: The maturation of microRNAs (miRNAs) successively undergoes Drosha, Dicer, and Argonaute -mediated processing, however, the intricate regulations of the individual miRNA maturation are largely unknown. Retinoid x receptor alpha (RXRα) belongs to nuclear receptors that regulate gene transcription by binding to DNA elements, however, whether RXRα binds to miRNAs to exert physiological functions is not known. RESULTS: In this work, we found that RXRα directly binds to the precursor of miR-103 (pre-miR-103a-2) via its DNA-binding domain with a preferred binding sequence of AGGUCA. The binding of RXRα inhibits the processing of miR-103 maturation from pre-miR-103a-2. Mechanistically, RXRα prevents the nuclear export of pre-miR-103a-2 for further processing by inhibiting the association of exportin-5 with pre-miR-103a-2. Pathophysiologically, the negative effect of RXRα on miR-103 maturation correlates to the positive effects of RXRα on the expression of Dicer, a target of miR-103, and on the inhibition of breast cancer. CONCLUSIONS: Our findings unravel an unexpected role of transcription factor RXRα in specific miRNA maturation at post-transcriptional level through pre-miRNA binding, and present a mechanistic insight regarding RXRα role in breast cancer progression.

Global, regional, and national temporal trends in metabolism-related ischemic stroke mortality and disability from 1990 to 2021.

BACKGROUND: Stroke ranks as the second leading cause of mortality and the third leading cause of disability worldwide. Nonetheless, the evolving burden of ischemic stroke attributable to various metabolic risk factors remains inadequately elucidated. A thorough grasp of these trends is crucial for a nuanced comprehension of stroke epidemiology and the formulation of effective preventive and interventional measures. METHOD: Based on the Global Burden of Disease, Injury, and Risk Factors Study 2021 (GBD), we analyzed national temporal trends in the burden of metabolism-associated ischemic stroke in 204 countries and territories globally from 1990-2021, as measured by the average annual percentage change (AAPC), using join-point regression models. The burden of disease was assessed using age-standardized (ASR) mortality rates and disability-adjusted life years (DALY) per 100 000 population. Cross-country inequalities in ischemic stroke burden were quantified using standard health equity methods and changes in ischemic stroke burden were projected to 2045. RESULTS: Globally, the ASR for ischemic stroke mortality linked to overall dietary metabolic risk declined by an average of 1.6% annually, while the ASR for disability-adjusted life years saw an average annual decrease of 1.3%. High systolic blood pressure remained a primary contributor to metabolism-related ischemic stroke, accounting for 57.9% of deaths and 58.0% of disability in 2021. Disparities associated with the sociodemographic index (SDI) diminished, with the gap in DALYs between countries with the highest and lowest SDIs narrowing from 592.2 (95% CI: 440.2-744.4) to 480.4 (95% CI: 309.7-651.2) in 2021. Projections indicate a continued decline in overall metabolism-related ischemic stroke deaths, mortality rates, and ASRs through 2045, although an increase in DALYs and ASRs is anticipated within the male population. CONCLUSION: The global burden of metabolic risk-associated ischemic stroke has generally been decreasing from 2019 to 2021. This study highlights significant challenges in controlling and managing metabolic risk-associated ischemic stroke, including an increase in the number of cases in certain countries and regions, as well as an uneven distribution worldwide. These findings may provide valuable insights for the development of improved public health policies and the rational allocation of healthcare resources.

Synergistic assessment of multi-scenario urban waterlogging through data-driven decoupling analysis in high-density urban areas: A case study in Shenzhen, China.

Extreme meteorological events and rapid urbanization have led to serious urban flooding problems. Characterizing spatial variations in flooding susceptibility and elucidating its driving factors are essential for preventing damages from urban pluvial flooding. However, conventional methods, limited by spatial heterogeneity and the intricate mechanisms of urban flooding, frequently demonstrated a deficiency in precision when assessing flooding susceptibility in dense urban areas. Therefore, this study proposed a novel framework for an integrated assessment of urban flood susceptibility, based on a comprehensive cascade modeling chain consisting of XGBoost, SHapley Additive exPlanations (SHAP), and Partial Dependence Plots (PDP) in combination with K-means. It aimed to recognize the specific influence of urban morphology and the spatial patterns of flooding risk agglomeration under different rainfall scenarios in high-density urban areas. The XGBoost model demonstrated enhanced accuracy and robustness relative to other three benchmark models: RF, SVR, and BPDNN. This superiority was effectively validated during both training and independent testing in Shenzhen. The results indicated that urban 3D morphology characteristics were the dominant factors for waterlogging magnitude, which occupied 46.02 % of relative contribution. Through PDP analysis, multi-staged trends highlighted critical thresholds and interactions between significant indicators like building congestion degree (BCD) and floor area ratio (FAR). Specifically, optimal intervals like BCD between 0 and 0.075 coupled with FAR values between 0.5 and 1 have the potential to substantially mitigate flooding risks. These findings emphasize the need for strategic building configuration within urban planning frameworks. In terms of the spatial-temporal assessment, a significant aggregation effect of high-risk areas that prone to prolonged duration or high-intensity rainfall scenarios emerged in the old urban districts. The approach in the present study provides quantitative insights into waterlogging adaptation strategies for sustainable urban planning and design.

A novel arterial coupler with non-return snap-fit connection approach optimized arterial end-to-end anastomotic technique: An experimental study.

PURPOSE: Hand-sewn anastomosis as the gold standard of vascular anastomosis cannot fully meet the requirements of vascular anastomosis in speed and quality. Various vascular couplers have been developed to ameliorate this situation. Most of them are mainly used for venous anastomosis rather than arterial anastomosis, even though it is generally acknowledged that in almost all operations involving vascular reconstruction, it is the arteries that need to be anastomosed faster and more accurately and not the veins. A dedicated device is needed for creating arterial anastomosis in an easy, timesaving, less damaging but reliable procedure. Therefore, we plan to develop a novel arterial coupler device and test pre-clinical safety and effectiveness. METHODS: In this cohort study, the rationality of this novel arterial coupler was preliminarily tested by finite element analysis before it was manufactured. Several factors restrict the use of vascular couplers in arterial anastomosis, such as arterial eversion, fixation, etc. The manufactured arterial couplers underwent in vitro and in vivo experiments. In vitro, isolated arteries of beagles were anastomosed with the assistance of an arterial coupler, and the anastomosed arteries were evaluated through anti-traction tests. In animal experiments, the bilateral femoral arteries of 5 beagles served as a control group. After dissection, the femoral artery on one side was randomly selected to be anastomosed with a quick arterial coupler (QAC) (QAC group), and the femoral artery on the other side was anastomosed by the same person using an end-to-end suture technique with a 6-0 Prolene suture (suture group). The bilateral femoral arteries of 5 beagles were used for coupler-assisted anastomosis and hand-sewn anastomosis in vivo, respectively. Success rate, blood loss, anastomotic time, clamp time, total operation time, and patency rate were recorded. The patency of anastomosed arteries was assessed using vascular Doppler ultrasound, electromagnetic flowmeter, and pathological examination (6 weeks after surgery). RESULTS: As a novel arterial coupler, QAC was successfully designed and manufactured by using poly lactic-co-glycolic acid raw materials and 3-dimensions printing technology. Its rationality was preliminarily tested through finite element analysis and related mechanical analysis methods. The isolated arteries were successfully anastomosed with the assistance of QAC in vitro testing, which showed good anti-traction properties. In animal studies, QAC-assisted arterial anastomosis has superior profiles compared to hand-sewn anastomosis in anastomotic time (7.80 ± 1.41 vs. 16.38 ± 1.04 min), clamp time (8.80 ± 1.41 vs. 14.14 ± 1.57 min), and total operation time (46.64 ± 2.38 vs. 51.96 ± 3.65 min). The results of electromagnetic flowmeter, vascular Doppler ultrasound, and pathological examination showed that QAC-assisted anastomotic arteries were superior to hand-sewn arteries in terms of postoperative blood flow (16.86 ± 3.93 vs. 10.36 ± 0.92 mL/min) and vascular patency in 6 weeks after surgery. CONCLUSION: QAC is a well-designed and easily maneuverable device specialized for end-to-end arterial anastomosis. Application of this device may decrease thermal ischemia time and improve the patency of anastomotic arteries, thus, improving outcomes.

Multi-objective optimization via evolutionary algorithm (MOVEA) for high-definition transcranial electrical stimulation of the human brain.

Designing a transcranial electrical stimulation (tES) strategy requires considering multiple objectives, such as intensity in the target area, focality, stimulation depth, and avoidance zone. These objectives are often mutually exclusive. In this paper, we propose a general framework, called multi-objective optimization via evolutionary algorithm (MOVEA), which solves the non-convex optimization problem in designing tES strategies without a predefined direction. MOVEA enables simultaneous optimization of multiple targets through Pareto optimization, generating a Pareto front after a single run without manual weight adjustment and allowing easy expansion to more targets. This Pareto front consists of optimal solutions that meet various requirements while respecting trade-off relationships between conflicting objectives such as intensity and focality. MOVEA is versatile and suitable for both transcranial alternating current stimulation (tACS) and transcranial temporal interference stimulation (tTIS) based on high definition (HD) and two-pair systems. We comprehensively compared tACS and tTIS in terms of intensity, focality, and steerability for targets at different depths. Our findings reveal that tTIS enhances focality by reducing activated volume outside the target by 60%. HD-tTIS and HD-tDCS can achieve equivalent maximum intensities, surpassing those of two-pair tTIS, such as 0.51 V/m under HD-tACS/HD-tTIS and 0.42 V/m under two-pair tTIS for the motor area as a target. Analysis of variance in eight subjects highlights individual differences in both optimal stimulation policies and outcomes for tACS and tTIS, emphasizing the need for personalized stimulation protocols. These findings provide guidance for designing appropriate stimulation strategies for tACS and tTIS. MOVEA facilitates the optimization of tES based on specific objectives and constraints, advancing tTIS and tACS-based neuromodulation in understanding the causal relationship between brain regions and cognitive functions and treating diseases. The code for MOVEA is available at https://github.com/ncclabsustech/MOVEA.

Explainable fMRI-based brain decoding via spatial temporal-pyramid graph convolutional network.

Brain decoding, aiming to identify the brain states using neural activity, is important for cognitive neuroscience and neural engineering. However, existing machine learning methods for fMRI-based brain decoding either suffer from low classification performance or poor explainability. Here, we address this issue by proposing a biologically inspired architecture, Spatial Temporal-pyramid Graph Convolutional Network (STpGCN), to capture the spatial-temporal graph representation of functional brain activities. By designing multi-scale spatial-temporal pathways and bottom-up pathways that mimic the information process and temporal integration in the brain, STpGCN is capable of explicitly utilizing the multi-scale temporal dependency of brain activities via graph, thereby achieving high brain decoding performance. Additionally, we propose a sensitivity analysis method called BrainNetX to better explain the decoding results by automatically annotating task-related brain regions from the brain-network standpoint. We conduct extensive experiments on fMRI data under 23 cognitive tasks from Human Connectome Project (HCP) S1200. The results show that STpGCN significantly improves brain-decoding performance compared to competing baseline models; BrainNetX successfully annotates task-relevant brain regions. Post hoc analysis based on these regions further validates that the hierarchical structure in STpGCN significantly contributes to the explainability, robustness and generalization of the model. Our methods not only provide insights into information representation in the brain under multiple cognitive tasks but also indicate a bright future for fMRI-based brain decoding.